Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 22, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm025
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Preconditioning Enhances Cell Survival and Differentiation of Stem Cells during Transplantation in Infarcted Myocardium
1 Department of Pathology and Laboratory Medicine, University of Cincinnati, Med Ctr. Cincinnati, OH 45267, U.S.A.
2 National Centre of Excellence in Molecular Biology, Punjab University, Lahore, Pakistan.
* Both authors contributed equally to this work
Address for correspondence: Muhammad Ashraf, Ph.D. Department of Pathology and laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way Cincinnati, OH 45267-0529, Phone: (513) 558-0145, Fax: (513) 558-0807, Email: Muhammad.Ashraf{at}Uc.Edu
Aims: We hypothesized that preconditioning (PC) with stromal-derived factor 1 alpha (SDF-1) significantly enhances cell survival, proliferation and engraftment of bone marrow-derived mesenchymal stem cells (MSCs) via SDF-1/CXCR4 signaling.
Methods: MSCs were cultured and then incubated in medium for 60 min without SDF-1 (control group) or with SDF-1 0.05 µg/ml (SDF-1 group) or CXCR4-selective antagonist, AMD 3100 (AMD) (5 µg/ml, AMD group) or SDF-1 and AMD (0.05 µg/ml, 5 µg/ml, respectively, SDF-1 + AMD group). MSCs were treated for 60 min, washed in normal medium, and then exposed to H2O2(100 µmol/l) for 60 min to determine the effects of various treatments on cell injury, viability, and proliferation. For in vivo studies, rats were grouped (n = 6) after left anterior descending coronary artery ligation to receive 20 µl Dulbecco's modified Eagle's medium (DMEM) without cells or with 5x105 non-preconditioned MSCs (control group), SDF-1 preconditioned MSCs (SDF-1 group), AMD (AMD group), or MSCs treated with SDF-1 plus AMD (SDF-1+AMD group). Heart function, infarct size, fibrosis and MSC proliferation and differentiation in infarcted myocardium were determined after 4 weeks.
Results: In vitro data showed a marked increase in cell viability and proliferation following SDF-1 PC. In vivo data in preconditioned group showed a robust cell proliferation, reduction in infarct size and fibrosis, and significant improvement in cardiac function. Effects of SDF-1 PC were abrogated by CXCR4 antagonist.
Conclusions: We conclude that preconditioning with the chemokine SDF-1 suppresses MSCs apoptosis, enhances their survival, engraftment, and vascular density, and improves myocardial function via SDF/CXCR4 signaling. Chemokine preconditioning is a novel approach to enhancing stem cell survival and regeneration of infarcted myocardium.
Time for primary review: 33 days
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